Depression is characterized by abnormal catecholamine function, neural arousal, and Na+ transport. (Na+,K+-ATPase, the basis of active transport of Na+ and K+, is important in the regulation of these systems, and is associated with the highly specific cardiac glycoside receptor (OGR). The OGR was recently shown to have an endogenous ligand (CGRL); the Principal Investigator has developed an assay for this important substance. In preliminary studies, the Principal Investigator has shown that norepinephrine (NE) stimulates ATPase in vivo, that chronic NE stimulation increases nerve-specific CGR binding, and that NE and CGR effects on ATPase conformation are antagonistic. The present study will use rats and man to study interactions between NE and CGR regulation and the role of the system in depression. Studies in rats will examine 1) the role of specific NE receptors in the stimulation of ATPase by NE in vivo, 2) the effects of chronic NE stimulation or inhibition, antidepressant drugs, and changes in NE or caloric intake or sensitivity of ATPase to NE stimulation and CGR levels in brain and plasma, 3) effects of inhibition of nerve and non-nerve ATPase on NE function, and 4) effects of locus coeruleus lesions and chemical sympathectomy with 6-hydroxydopamine on CGRL. Studies in man will 1) examine effects of fasting, overfeeding, and increased or decreaded Na+ intake on plasma CGRL in normal man and 2) compare depressed patients, before and after treatment, with age- and sex- matched controls with respect to plasma CGRL and to sensitivity of their ATPase to normal CGRL in vitro. Future studies will examine the system in order possibly related disorders including mania, obesity, alcoholism, and arousal disorders, and will compare the regulation of the system by Na+ and by caloric intake in normals to that in patients.